The interaction of phencyclidine (PCP) and its analogs, opioid agonists and antagonists (including enkephalins) and channel drugs (amantadine, histrionicotoxin) with receptor-channel complexes at nicotinic (neuromuscular), muscarinic, glutaminergic and gabaergic synapses and their effect on electrical excitability of skeletal muscle membrane and squid giant axon will be evaluated with both biophysical and biochemical techniques. The site and mechanism of action of these drugs on receptor-channel complexes, the similarity of action between receptor-channel types and on the electrical properties of membranes will be determined by analysis of: 1) contractile; 2) electrical (cable properties, action potentials, spontaneous and evoked transmitter release, endplate and miniature endplate currents, acetylcholine noise analysis); and 3) chemosensitive properties of frog, rat, locust and lobster skeletal muscles. The structural requirements for channel action of PCPs and opioids will be determined and quantified to define drug-channel interactions and the nature of the channel site of action regardless of receptor type. The various channel drugs will be examined utilizing both biophysical and biochemical techniques to evaluate the identity of site of action within the channel and their ability to reverse PCPS interaction with its channel site, and thus to develop a rationale basis for reversal of PCP intoxication. A comparison will be made of the paradoxical ability of PCP and histrionicotoxin to depress acetylcholine-induced noise without affecting spontaneous and evoked responses while the reverse is apparent or morphine. The ability of PCP analogs, opioids and their antagonists to share this effect may resolve the existance of distinct receptors and channel populations at the nicotinic neuromuscular junction. The mechanism by which PCP blocks potassium conductance and prolongs action potentials is of major significance to central and peripheral transmitter processes and will be fully examined to explain the abnormal muscle strength and psychological behavior in humans with peripheral studies and concomittant studies in identified central neurons in culture.